2,3-disubstituted pyrazinesulfonamides as CRTH2 inhibitors

a technology of pyrazine sulfonamide and pyrazine sulfonamide, which is applied in the direction of respiratory disorder, organic active ingredients, digestive system, etc., can solve the problems of low efficacy, indirect link between dp receptor activation and pgd2-stimulated eosinophil migration,

Inactive Publication Date: 2014-08-05
MERCK SERONO SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite intense interest in the role of PGD2 in the inflammatory response, a direct link between DP receptor activation and PGD2-stimulated eosinophil migration has not been established (Woodward et al.
However, the usefulness of these agents is often limited by side effects and low efficacy.

Method used

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  • 2,3-disubstituted pyrazinesulfonamides as CRTH2 inhibitors
  • 2,3-disubstituted pyrazinesulfonamides as CRTH2 inhibitors
  • 2,3-disubstituted pyrazinesulfonamides as CRTH2 inhibitors

Examples

Experimental program
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Effect test

example 1

General Procedure for the Synthesis of 2,3-Substituted Pyrazine Sulfonamide Derivatives of General Formula I, with A and Z as Above Defined (Schemes 1, 4, 5, 6, 7, 8, 9 and 10): N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzene-sulfonamide

[0239]

Method A:

[0240]To a solution of 1H-Indole (234 mg, 2.0 mmol, 1 eq) in dimethylformamide (10 mL) was added sodium hydride (80 mg, 2 mmol, 1 eq). After the evolution of hydrogen ceased, N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzene sulfonamide (intermediate 26) (854 mg, 2 mmol, 1 eq) in dimethylformamide (5 mL) was added and the reaction mixture heated to 80 degrees over 3 hours. The reaction was cooled, diluted with 30 mL of water and extracted with diethyl ether. The organic layer was dried over MgSO4, evaporated and purified by flash chromatography on silica gel eluting with AcOEt and cyclohexane to give pure N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfona...

example 2

2-chloro-N-{3-[4-({methyl[4-(trifluoromethoxy)phenyl]amino}-methyl)-phenyl]pyrazin-2-yl}benzene sulfonamide

[0243]

[0244]Following the general methods as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and N-methyl-4-(trifluoromethoxy)aniline, the title compound was isolated as a yellow solid in 72% yield (99% purity by HPLC).

[0245]MS (ESI+): 550.1; MS (ESI−): 547.8.

example 3

N-(3-{4-[(2-ethyl-1H-benzimidazol-1-yl)methyl]phenyl}pyrazin-2-yl)-2-(trifluoromethyl)benzenesulfonamide

[0246]

[0247]Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2-ethylbenzimidazole, the title compound was isolated as a yellow solid in 63% yield (96% purity by HPLC).

[0248]MS (ESI+): 538.6; MS (ESI−): 536.5.

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Abstract

The present invention is related to the use of 2,3 substituted pyrazine sulfonamides of formula (I)for the treatment and / or prevention of allergic diseases, inflammatory dermatoses and other diseases with an inflammatory component. Specifically, the present invention is related to the use of 2,3 substituted pyrazine sulfonamides for the modulation, notably the inhibition, of CRTH2 activity.

Description

[0001]The present application is filed under 35 U.S.C. §371 as a U.S. national phase application of PCT application no. PCT / EP2006 / 061706, which was filed Apr. 20, 2006. The aforementioned PCT application claimed benefit of priority of EP 05103254.8, which was filed Apr. 21, 2005 and U.S. 60 / 675,381, which was filed Apr. 27, 2005. The entire text of each of the aforementioned applications is incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to 2,3 substituted pyrazine sulfonamides for use as pharmaceutical active compounds, as well as pharmaceutical formulations containing such 2,3 substituted pyrazine sulfonamides. Said derivatives are useful for the treatment and / or prevention of allergic diseases and inflammatory dermatoses. Specifically, the present invention is related to the use of 2,3 substituted pyrazine sulfonamides for the modulation, notably the inhibition of CRTH2 activity. The present invention furthermore relates to novel 2,3 su...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/4965C07D241/22C07D401/10C07D401/12C07D403/10C07D405/12C07D409/12C07D413/10
CPCC07D241/22C07D409/12C07D401/10C07D413/10C07D405/12C07D403/10C07D401/12C07D403/06C07D403/12C07D403/14C07D409/14C07D411/14C07D413/12C07D417/10C07D417/12C07D241/20A61P1/04A61P11/02A61P11/06A61P17/00A61P17/04A61P19/02A61P25/00A61P25/04A61P25/28A61P27/14A61P29/00A61P37/00A61P37/02A61P37/08A61P43/00C07D211/24A61K31/4965
Inventor PAGE, PATRICKSCHWARZ, MATTHIASSEBILLE, ERICCLEVA, CHRISTOPHEMERLOT, CEDRICMAIO, MAURIZIO
Owner MERCK SERONO SA
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